Journal Article

Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease

Feistritzer, Clemens, Grabherr, Felix, Enrich, Barbara, Oberhuber, Georg, Kaser, Arthur, Gehmacher, Thomas, He, Gui-Wei, Weiss, Günter, Przysiecki, Nicole, Tancevski, Ivan, Effenberger, Maria, Gerner, Romana R., Rosenstiel, Philip, Reitmeier, Isabelle, Mayr, Lisa, Sommer, Felix, Niederreiter, Lukas, Ran, Qitao, Kunz, Kai T. R., Adolph, Timon E., Ruder, Barbara, Keller, Markus A., Koch, Robert, Zoller, Heinz, Moschen, Alexander R., Haschka, David, Tilg, Herbert, Becker, Christoph, Schwärzler, Julian, Seifert, Markus, Sprung, Susanne, Tymoszuk, Piotr, Hilbe, Richard

2020

Overview

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn’s disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD. Dietary lipids are linked to the development of inflammatory bowel diseases through unclear mechanisms. Here, the authors report that dietary polyunsaturated fatty acids trigger intestinal inflammation resembling aspects of Crohn’s disease, which is restricted by glutathione peroxidase 4 in the intestinal epithelium.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 631/250 / 692/4020/1503/257 / 82/51 / Adult / Animals / Arachidonic acid / Cell death / Cell Death - genetics / Cell Death - physiology / Crohn Disease - genetics / Crohn Disease - metabolism / Crohn's disease / Cytokines / Dietary Fats - adverse effects / Disease / Enteritis / Enteritis - etiology / Enteritis - genetics / Enteritis - metabolism / Epithelial cells / Epithelium / Fatty acids / Fatty Acids, Unsaturated - genetics / Fatty Acids, Unsaturated - metabolism / Female / Ferroptosis / Glutathione / Glutathione peroxidase / Glutathione Peroxidase - metabolism / Granuloma / Humanities and Social Sciences / Humans / Inflammation - genetics / Inflammation - metabolism / Inflammatory bowel disease / Inflammatory bowel diseases / Intestine / Leukocytes (neutrophilic) / Lipid peroxidation / Lipid Peroxidation - genetics / Lipid Peroxidation - physiology / Lipids / Male / Mice / Mice, Inbred C57BL / Middle Aged / Mucosa / multidisciplinary / Peroxidase / Peroxidation / Phospholipid Hydroperoxide Glutathione Peroxidase - genetics / Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism / Polyunsaturated fatty acids / Science / Science (multidisciplinary)